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The progesterone metabolite allopregnanolone (Allo) is a positive GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor modulating steroid with potent effects. In humans, disorders such as premenstrual dysphoric disorder (PMDD), hepatic encephalopathy and polycystic ovarian syndrome are associated with elevated Allo levels and increased negative mood, disturbed memory and increased food intake in some individuals. This is surprising because Allo shares many properties with benzodiazepines and is mainly considered to be anxiolytic and anti\u2010depressant. However, it is well established that, in certain individuals, GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor activating compounds could have paradoxical effects and thus be anxiogenic in low physiological plasma concentrations but anxiolytic at high levels. We have demonstrated that isoallopregnanolone (Isoallo), the 3\u03b2\u2010OH sibling of Allo, functions as a GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor modulating steroid antagonist (GAMSA) but without any effects of its own on GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptors. The antagonistic effect is noted in most GABA\n                    <jats:sub>A<\/jats:sub>\n                    subtypes investigated in vitro to date. In vivo, Isoallo can inhibit Allo\u2010induced anaesthesia in rats, as well as sedation or saccadic eye velocity in humans. Isoallo treatment has been studied in women with PMDD. In a first phase II study, Isoallo (Sepranolone; Asarina Pharma) injections significantly ameliorated negative mood in women with PMDD compared with placebo. Several GAMSAs for oral administration have also been developed. The GAMSA, UC1011, can inhibit Allo induced memory disturbances in rats and an oral GAMSA, GR3027, has been shown to restore learning and motor coordination in rats with hepatic encephalopathy. In humans, vigilance, cognition and pathological electroencephalogram were improved in patients with hepatic encephalopathy on treatment with GR3027. In conclusion GAMSAs are a new possible treatment for disorders and symptoms caused by hyperactivity in the GABA\n                    <jats:sub>A<\/jats:sub>\n                    system.\n                  <\/jats:p>","DOI":"10.1111\/jne.13013","type":"journal-article","created":{"date-parts":[[2021,7,12]],"date-time":"2021-07-12T12:01:39Z","timestamp":1626091299000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Positive GABA\n                    <sub>A<\/sub>\n                    receptor modulating steroids and their antagonists: Implications for clinical treatments"],"prefix":"10.1111","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0907-3535","authenticated-orcid":false,"given":"Torbj\u00f6rn","family":"B\u00e4ckstr\u00f6m","sequence":"first","affiliation":[{"name":"Department of Clinical Sciences, Obstetrics and Gynecology Ume\u00e5 University  Umea Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roshni","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Integrative Medical Biology Ume\u00e5 University  Umea Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4988-1967","authenticated-orcid":false,"given":"Marie","family":"Bixo","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Obstetrics and Gynecology Ume\u00e5 University  Umea Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2016.04.003"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.10.4553"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2005.04.007"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(97)00455-1"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2006.02.002"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006842-198312000-00004"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3109\/00016348809004191"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1530\/acta.0.1250132"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00737-013-0346-y"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/09513590701253511"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2015.246"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-016-4258-1"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4530(97)00064-4"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.155.7.910"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.159.1.145"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.60.2.161"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3956(03)00109-2"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31264-3"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1815981"},{"key":"e_1_2_10_21_1","unstructured":"Sage Therapeutics Reports Topline Results from Pivotal Phase 3 MOUNTAIN Study of SAGE\u2010217 in Major Depressive Disorder. 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